Prognostic and therapeutic significance of COP9 signalosome subunit CSN5 in prostate cancer (2025)

前列腺癌生物 COP9信号体癌症研究癌症蛋白质亚单位前列腺遗传学生物化学基因酶蛋白酶肽水解酶类

作者

Ying Z. Mazzu,YuRou Liao,Subhiksha Nandakumar,Lina Jehane,Richard P. Koche,Sai Harisha Rajanala,Ruifang Li,HuiYong Zhao,Travis Gerke,Goutam Chakraborty,Gwo‐Shu Mary Lee,Gouri J. Nanjangud,Anuradha Gopalan,Yu Chen,Philip W. Kantoff

出处

期刊：Oncogene [Springer Nature]
日期：2021-11-20 卷期号：41 (5): 671-682 被引量：11

链接

nih.gov nih.govdoi.org

标识

DOI：10.1038/s41388-021-02118-4

摘要

Chromosome 8q gain is associated with poor clinical outcomes in prostate cancer, but the underlying biological mechanisms remain to be clarified. CSN5, a putative androgen receptor (AR) partner that is located on chromosome 8q, is the key subunit of the COP9 signalosome, which deactivates ubiquitin ligases. Deregulation of CSN5 could affect diverse cellular functions that contribute to tumor development, but there has been no comprehensive study of its function in prostate cancer. The clinical significance of CSN5 amplification/overexpression was evaluated in 16 prostate cancer clinical cohorts. Its oncogenic activity was assessed by genetic and pharmacologic perturbations of CSN5 activity in prostate cancer cell lines. The molecular mechanisms of CSN5 function were assessed, as was the efficacy of the CSN5 inhibitor CSN5i-3 in vitro and in vivo. Finally, the transcription cofactor activity of CSN5 in prostate cancer cells was determined. The prognostic significance of CSN5 amplification and overexpression in prostate cancer was independent of MYC amplification. Inhibition of CSN5 inhibited its oncogenic function by targeting AR signaling, DNA repair, multiple oncogenic pathways, and spliceosome regulation. Furthermore, inhibition of CSN5 repressed metabolic pathways, including oxidative phosphorylation and glycolysis in AR-negative prostate cancer cells. Targeting CSN5 with CSN5i-3 showed potent antitumor activity in vitro and in vivo. Importantly, CSN5i-3 synergizes with PARP inhibitors to inhibit prostate cancer cell growth. CSN5 functions as a transcription cofactor to cooperate with multiple transcription factors in prostate cancer. Inhibiting CSN5 strongly attenuates prostate cancer progression and could enhance PARP inhibition efficacy in the treatment of prostate cancer.

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